Studying interactions among anthropogenic stressors in freshwater ecosystems: A systematic review of 2396 multiple-stressor experiments.

Understanding the interactions among anthropogenic stressors is critical for effective conservation and management of ecosystems. Freshwater scientists have invested considerable resources in conducting factorial experiments to disentangle stressor interactions by testing their individual and combined effects. However, the diversity of stressors and systems studied has hindered previous syntheses of this body of research. To overcome this challenge, we used a novel machine learning framework to identify relevant studies from over 235,000 publications. Our synthesis resulted in a new dataset of 2396 multiple-stressor experiments in freshwater systems. By summarizing the methods used in these studies, quantifying trends in the popularity of the investigated stressors, and performing co-occurrence analysis, we produce the most comprehensive overview of this diverse field of research to date. We provide both a taxonomy grouping the 909 investigated stressors into 31 classes and an open-source and interactive version of the dataset (https://jamesaorr.shinyapps.io/freshwater-multiple-stressors/). Inspired by our results, we provide a framework to help clarify whether statistical interactions detected by factorial experiments align with stressor interactions of interest, and we outline general guidelines for the design of multiple-stressor experiments relevant to any system. We conclude by highlighting the research directions required to better understand freshwater ecosystems facing multiple stressors.

Regional hyperthermia for soft tissue sarcoma - a survey on current practice, controversies and consensus among 12 European centers.

PURPOSE: To analyze the current practice of regional hyperthermia (RHT) for soft tissue sarcoma (STS) at 12 European centers to provide an overview, find consensuses and identify controversies necessary for future guidelines and clinical trials. METHODS: In this cross-sectional survey study, a 27-item questionnaire assessing clinical subjects and procedural details on RHT for STS was distributed to 12 European cancer centers for RHT. RESULTS: We have identified seven controversies and five consensus points. Of 12 centers, 6 offer both, RHT with chemotherapy (CTX) or with radiotherapy (RT). Two centers only offer RHT with CTX and four centers only offer RHT with RT. All 12 centers apply RHT for localized, high-risk STS of the extremities, trunk wall and retroperitoneum. However, eight centers also use RHT in metastatic STS, five in palliative STS, eight for superficial STS and six for low-grade STS. Pretherapeutic imaging for RHT treatment planning is used by 10 centers, 9 centers set 40-43 °C as the intratumoral target temperature, and all centers use skin detectors or probes in body orifices for thermometry. DISCUSSION: There is disagreement regarding the integration of RHT in contemporary interdisciplinary care of STS patients. Many clinical controversies exist that require a standardized consensus guideline and innovative study ideas. At the same time, our data has shown that existing guidelines and decades of experience with the technique of RHT have mostly standardized procedural aspects. CONCLUSIONS: The provided results may serve as a basis for future guidelines and inform future clinical trials for RHT in STS patients.

Reconstructing historical time-series of cyanobacteria in lake sediments: Integrating technological innovation to enhance cyanobacterial management.

The global rise of cyanobacterial blooms emphasizes the need to develop tools to manage water bodies prone to cyanobacterial dominance. Reconstructing cyanobacterial baselines and identifying environmental drivers that favour cyanobacterial dominance are important to guide management decisions. Conventional techniques for estimating cyanobacteria in lake sediments require considerable resources, creating a barrier to routine reconstructions of cyanobacterial time-series. Here, we compare a relatively simple technique based on spectral inferences of cyanobacteria using visible near-infrared reflectance spectroscopy (VNIRS) with a molecular technique based on real-time PCR quantification (qPCR) of the 16S rRNA gene conserved in cyanobacteria in 30 lakes across a broad geographic gradient. We examined the sedimentary record from two perspectives: 1) relationships throughout the entire core (without radiometric dating); 2) relationships post-1900s with the aid of radiometric dating (i.e., 210Pb). Our findings suggest that the VNIRS-based cyanobacteria technique is best suited for reconstructing cyanobacterial abundance in recent decades (i.e., circa 1990 onwards). The VNIRS-based cyanobacteria technique showed agreement with those generated using qPCR, with 23 (76%) lakes showing a strong or very strong positive relationship between the results of the two techniques. However, five (17%) lakes showed negligible relationships, suggesting cyanobacteria VNIRS requires further refinement to understand where VNIRS is unsuitable. This knowledge will help scientists and lake managers select alternative cyanobacterial diagnostics where appropriate. These findings demonstrate the utility of VNIRS, in most instances, as a valuable tool for reconstructing past cyanobacterial prevalence.

Human Norovirus Surrogates Persist in Nontraditional Sources of Irrigation Water in Excess of 100 Days.

Human norovirus (HuNoV) has been implicated as the leading cause of foodborne illness worldwide. The ability of HuNoV to persist in water can significantly impact food safety as agriculture and processing water could serve as vehicles of virus transmission. This study focused on the persistence and infectivity of the HuNoV surrogate viruses, murine norovirus (MNV), and Tulane virus (TV), after prolonged storage in diverse environmental water types currently used for agricultural irrigation. In this study, vegetable processing water (VW), brackish tidal surface water (SW), municipal reclaimed water (RW), and pond water (PW) were inoculated with each virus in a 1:10 v/v ratio containing virus at 3.5-4.5 logPFU/mL and stored at 16°C for 100 days. This time and temperature combination was chosen to mimic growing and harvest conditions in the mid-Atlantic area of the United States. Samples were then assayed for the presence of viral RNA using reverse transcription-quantitative polymerase chain reaction (RT-qPCR) approximately weekly throughout the study. Persistence of MNV and TV was not significantly different (p > 0.05) from one another in any water sample (n = 7) or the control (HBSS). However, there was variability observed in viral persistence across water samples with significant differences observed between several water samples. The presence of intact viral capsids enclosing the genomes of MNV and TV were evaluated by an RNase assay coupled with RT-qPCR on specific timepoints and determined to be intact up to and at 100 days after inoculation. TV was also shown to remain infectious in a cell culture assay (TCID50) up to 100 days of incubation. These findings are significant in that the potential for not only detection of enteric viruses can occur long after a contamination event occurs but these viruses may also remain infectious.

Congenital Synostosis of the Knee: Long-term Outcomes of Limb Reconstruction Surgery.

BACKGROUND: Congenital synostosis of the knee is a rare condition with limited data on treatment options and outcomes. This study reports clinical findings, treatment approach, and surgical/clinical outcomes for congenital synostosis of the knee. METHODS: An institutional review board-approved retrospective review of patients with congenital synostosis of the knee presenting to 2 institutions between 1997 and 2021 was performed. RESULTS: Eight patients (13 knees) with a median follow-up of 11.3 years (3.3 to 17 y) were included. Seven patients had associated syndromes. Patients presented with an average knee flexion deformity of 100° (range 60 to 130°) and delayed walking ability. Seven patients had associated upper extremity hypoplasia/phocomelia. The average age at the index surgery was 4.3 years (range 1.2 to 9.2 y). Synostosis resection with gradual deformity correction was performed in most patients. An attempt was made at a mobile knee in some patients, but all went on to knee fusion. Mean flexion deformity at final follow-up was 11.6° (range: 0 to 40°) and 5 limbs were fused in full extension. Mean limb length discrepancy at final follow-up was 6.8 cm (range: 0 to 8 cm). All patients maintained their improved ambulation status at final follow-up. Twenty-two complications were identified. CONCLUSIONS: Reliable correction of the deformity associated with congenital knee synostosis was achieved at a median follow-up of 11 years. Importantly, all patients maintained their improved ambulation at final follow-up. This is the largest study on patients with congenital knee synostosis and outlines a reconstructive approach to improve ambulatory status. LEVEL OF EVIDENCE: Level IV.

Spatial predictors and temporal forecast of total organic carbon levels in boreal lakes.

Browning of Fennoscandian boreal lakes is raising concerns for negative ecosystem impacts as well as reduced drinking water quality. Declined sulfur deposition and warmer climate, along with afforestation, other climate impacts and less outfield grazing, have resulted in increased fluxes of Total Organic Carbon (TOC) from catchments to freshwater, and subsequently to coastal waters. This study assesses the major governing factors for increased TOC levels among several catchment characteristics in almost 5000 Fennoscandian lakes and catchments. Normalized Difference Vegetation Index (NDVI), a proxy for plant biomass, and the proportions of peatland in the catchment, along with surface runoff intensity and nitrogen deposition loading, were identified as the main spatial predictors for lake TOC concentrations. A multiple linear model, based on these explanatory variables, was used to simulate future TOC concentration in surface runoff from coastal drainage basins in 2050 and 2100, using the forecasts of climatic variables in two of the Shared Socio-economic Pathways (SSP): 1-2.6 (+2 °C) and 3-7.0 (+4,5 °C). These scenarios yield contrasting effects. SSP 1-2.6 predicts an overall decrease of TOC export to coastal waters, while SSP 3-7.0 in contrast leads to an increase in TOC export.

Vitamin B12 Deficiency (Un-)Detected Using Newborn Screening in Norway.

Untreated vitamin B12 (B12) deficiency may cause delayed development in infants. Several newborn screening (NBS) programs have reported an increased detection rate of B12 deficiency when second-tier dried blood spot (DBS) analyses of total homocysteine (tHcy) and methylmalonic acid (MMA) are included. This is a retrospective study of newborns reported from NBS during 2012−2021 with confirmed B12 deficiency. DBSs were retrieved from the NBS biobank for second-tier MMA and tHcy analysis. Thirty-one newborns were diagnosed with B12 deficiency out of 552970 screened. Twenty-five were ascertained from sixty-one false positive (FP) cases of methylmalonic acidemia and propionic acidemia (PA), and six infants screened positive for other NBS metabolic diseases with propionylcarnitine (C3) in the normal range. In the original DBS, 7/23 (30%) and 12/23 (52%) of B12-deficient newborns with FP methylmalonic acidemia/PA had MMA and tHcy > 99th percentile. B12 deficiency was a common differential diagnosis of screening positive for methylmalonic and PA. C3 failed to identify a subset of newborns with B12 deficiency. Second-tier MMA and tHcy analyses in the DBS showed suboptimal sensitivity for identifying infants with B12 deficiency. The shortcomings of NBS should be acknowledged when considering B12 deficiency as a primary target of NBS panels.

Regional hyperthermia with cisplatin added to gemcitabine versus gemcitabine in patients with resected pancreatic ductal adenocarcinoma: The HEAT randomised clinical trial.

BACKGROUND: Regional hyperthermia (RHT) with cisplatin added to gemcitabine showed efficacy in gemcitabine-pre-treated patients with advanced pancreatic ductal adenocarcinoma. We conducted a randomised clinical trial to investigate RHT with cisplatin added to gemcitabine (GPH) compared with gemcitabine (G) in the adjuvant setting of resected pancreatic ductal adenocarcinoma. METHODS: This randomised, multicentre, open-label trial randomly assigned patients to either GPH (gemcitabine 1000 mg/m2 on day 1, 15 and cisplatin 25 mg/m2 with RHT on day 2, 3 and 15,16) or to G (gemcitabine 1000 mg/m2 on day 1,8,15), four-weekly over six cycles. Disease-free survival (DFS) was the primary end-point. Secondary end-points included overall survival (OS) and safety. RESULTS: A total of 117 eligible patients (median age, 63 years) were randomly allocated to treatment (57 GPH; 60 G). With a follow-up time of 56.6 months, the median DFS was 12.7 compared to 11.2 months for GPH and G, respectively (p = 0.394). Median post-recurrence survival was significantly prolonged in the GPH-group (15.3 versus 9.8 months; p = 0.031). Median OS reached 33.2 versus 25.2 months (p = 0.099) with 5-year survival rates of 28.4% versus 18.7%. Excluding eight patients who received additional capecitabine in the G-arm (investigators choice), median OS favoured GPH (p = 0.052). Adverse events CTCAE (Common Terminology Criteria for Adverse Events) grade ≥3 occurred in 61.5% (GPH) versus 63.6% (G) of patients. Two patients in the G-group died because of treatment-related toxic effects. CONCLUSIONS: The randomised controlled Hyperthermia European Adjuvant Trial study failed to demonstrate a significant difference in DFS. However, it suggests a difference in post-recurrence survival and a trend for improved OS. CLINICALTRIALS: gov, number NCT01077427.

Diffusion-weighted MRI with deep learning for visualizing treatment results of MR-guided HIFU ablation of uterine fibroids.

OBJECTIVES: No method is available to determine the non-perfused volume (NPV) repeatedly during magnetic resonance-guided high-intensity focused ultrasound (MR-HIFU) ablations of uterine fibroids, as repeated acquisition of contrast-enhanced T1-weighted (CE-T1w) scans is inhibited by safety concerns. The objective of this study was to develop and test a deep learning-based method for translation of diffusion-weighted imaging (DWI) into synthetic CE-T1w scans, for monitoring MR-HIFU treatment progression. METHODS: The algorithm was retrospectively trained and validated on data from 33 and 20 patients respectively who underwent an MR-HIFU treatment of uterine fibroids between June 2017 and January 2019. Postablation synthetic CE-T1w images were generated by a deep learning network trained on paired DWI and reference CE-T1w scans acquired during the treatment procedure. Quantitative analysis included calculation of the Dice coefficient of NPVs delineated on synthetic and reference CE-T1w scans. Four MR-HIFU radiologists assessed the outcome of MR-HIFU treatments and NPV ratio based on the synthetic and reference CE-T1w scans. RESULTS: Dice coefficient of NPVs was 71% (± 22%). The mean difference in NPV ratio was 1.4% (± 22%) and not statistically significant (p = 0.79). Absolute agreement of the radiologists on technical treatment success on synthetic and reference CE-T1w scans was 83%. NPV ratio estimations on synthetic and reference CE-T1w scans were not significantly different (p = 0.27). CONCLUSIONS: Deep learning-based synthetic CE-T1w scans derived from intraprocedural DWI allow gadolinium-free visualization of the predicted NPV, and can potentially be used for repeated gadolinium-free monitoring of treatment progression during MR-HIFU therapy for uterine fibroids. KEY POINTS: • Synthetic CE-T1w scans can be derived from diffusion-weighted imaging using deep learning. • Synthetic CE-T1w scans may be used for visualization of the NPV without using a contrast agent directly after MR-HIFU ablations of uterine fibroids.

Engaging men in maternal, infant and young child nutrition in rural Tanzania: Outcomes from a cluster randomized control trial and qualitative study.

There is growing recognition that engaging men in maternal, infant and young child nutrition (MIYCN) interventions can benefit child health and disrupt harmful gender norms. We conducted a cluster-randomized controlled trial in Tanzania, which engaged men and women in behaviour change via mobile messaging (short message service [SMS]) and traditional interpersonal communication (IPC), separately and in combination. Here, we evaluate intervention effects on individual-level men's MIYCN knowledge and discuss barriers to male engagement. Eligible clusters were dispensary catchment areas with >3000 residents. Forty clusters were stratified by population size and randomly allocated to the four study arms, with 10 clusters per arm. Data on knowledge and intervention exposure were collected from 1394 men through baseline and endline surveys (March-April 2018 and July-September 2019). A process evaluation conducted partway through the 15-18-month intervention period included focus group discussions and interviews. Data were analysed for key trends and themes using Stata and ATLAS.ti software. Male participants in the short message service + interpersonal communication (SMS + IPC) group reported higher exposure to IPC discussions than IPC-only men (43.8% and 21.9%, respectively). Knowledge scores increased significantly across all three intervention groups, with the greatest impact in the SMS + IPC group. Qualitative findings indicated that the main barriers to male participation were a lack of interest in health/nutrition and perceptions that these topics were a woman's responsibility. Other challenges included meeting logistics, prioritizing income-earning activities and insufficient efforts to engage men. The use of a combined approach fusing IPC with SMS is promising, yet countering gender norms and encouraging stronger male engagement may require additional strategies.

Local stressors mask the effects of warming in freshwater ecosystems.

Climate warming is a ubiquitous stressor in freshwater ecosystems, yet its interactive effects with other stressors are poorly understood. We address this knowledge gap by testing the ability of three contrasting null models to predict the joint impacts of warming and a range of other aquatic stressors using a new database of 296 experimental combinations. Despite concerns that stressors will interact to cause synergisms, we found that net impacts were usually best explained by the effect of the stronger stressor alone (the dominance null model), especially if this stressor was a local disturbance associated with human land use. Prediction accuracy depended on stressor identity and how asymmetric stressors were in the magnitude of their effects. These findings suggest we can effectively predict the impacts of multiple stressors by focusing on the stronger stressor, as habitat alteration, nutrients and contamination often override the biological consequences of higher temperatures in freshwater ecosystems.

Assessing Heavy Metal Pollution of the Largest Nature Reserve in Tianjin City, China.

Beidagang Wetland (BW) Nature Reserve is centrally situated in Tianjin City, experiencing an extreme industrial development. This study uses index characteristic analysis systems for assessing the individual and combined heavy metal pollution loading in the water during the spring and autumn seasons. By combining the pollution level of single pollutant, a more comprehensive evaluation of water quality in BW was achieved. Water quality was worst during autumn due to high level of Cd and Pb, which indicate the type of anthropogenic activities have a serious effect on heavy metal pollution in BW. In addition, high exchangeable amounts of Cd (> 40%) were found in the sediments of BW, indicating Cd pollution has emerged. There is a need for appropriate abatement actions curbing heavy metal loading and improving water quality of the BW Nature Reserve, thereby ensuring a sustainable management of its ecosystem services.

Increased MR-guided high intensity focused ultrasound (MR-HIFU) sonication efficiency of uterine fibroids after carbetocin administration.

Purpose: We investigated whether administration of the long-acting uterus stimulant carbetocin increased intra-subject sonication efficiency during Magnetic Resonance image guided High Intensity Focused Ultrasound (MR-HIFU) treatment of uterine fibroids. Method: In this prospective cohort study, thirty women with symptomatic uterine fibroids undergoing MR-HIFU treatment were included between January 2018 and January 2019. Treatment started with three sonications on one side of the uterine fibroid. Subsequently, one ampoule of 1 mL carbetocin (100 µg/mL) was administered intravenously and treatment continued with three sonications on the other side of the uterine fibroid. We compared the intra-subject sonication efficiency, in terms of Energy Efficiency Factor (EEF), thermal dose volume and sonication time to ablate one cm3 of fibroid tissue, before and after carbetocin administration. Adverse events that occurred within 30 min after carbetocin administration were recorded. Results: Sonication efficiency improved after carbetocin administration as indicated by a significant decrease in EEF and sonication time (p = 0.006 and p = 0.001 respectively), and a significant increase in thermal dose volume reached (p = <0.001). Five women (16.7%) experienced temporary tachycardia, one women in combination with headache, within 30 min after carbetocin administration. Conclusion: Administration of the long-acting uterus stimulant carbetocin improved the MR-HIFU treatment intra-subject sonication efficiency in women with symptomatic uterine fibroids.

VISTA in Soft Tissue Sarcomas: A Perspective for Immunotherapy?

(1) Background: V domain immunoglobulin suppressor of T cell activation (VISTA) plays a critical role in antitumor immunity and may be a valuable target in cancer immunotherapy. To date, it has never been studied in a large and well-characterised cohort of soft tissue sarcomas (STS). (2) Methods: Using immunohistochemistry, we examined VISTA expression in tumour tissues of 213 high-risk STS. We then analysed whether VISTA was associated with other clinicopathological parameters, including tumour-infiltrating lymphocyte (TIL) counts, programmed death receptor-1 (PD1), programmed death ligand-1 (PDL1), CD3, grading, and long-term survival. (3) Results: We observed VISTA expression in 96 (45%) of 213 specimens with distinct patterns ranging from 26 to 63% for histological subtypes. VISTA was associated with higher grade (G3 vs. G2, p = 0.019), higher TIL counts (p = 0.033), expression of PD1 (p = 0.046), PDL1 (p = 0.031), and CD3+ (p = 0.023). In patients without CD3+ TILs, 10-year survival was higher when VISTA was expressed compared to when there was no VISTA expression (p = 0.013). In a multivariate analysis, VISTA expression was independently associated with prolonged survival (p = 0.043). (4) Conclusions: VISTA is expressed in different STS subtypes and is associated with increased TILs, PD-1, PD-L1, and CD3 expression. Patients with VISTA+ tumours show improved survival. These results may help define future immunotherapeutic approaches in STS.

Polyethylene terephthalate and di-(2-ethylhexyl) phthalate in surface and core sediments of Bohai Bay, China: Occurrence and ecological risk.

Bohai Bay, a typical semi-enclosed bay, is close to the Beijing-Tianjin-Hebei Region, the economic center of north China. The release of emerging contaminants was considerably increasing with the fast urbanization and industrialization along the coastline. However, such data, e.g. plastic polymers, are still limited. Here, polyethylene terephthalate (PET) and di-(2-ethylhexyl) phthalate (DEHP) in surface sediments and sediment cores from the coastal area of Bohai Bay were investigated. The ranges of PET and DEHP concentrations in surface sediments are 1.49-13.90 mg/kg and 0.23-19.26 mg/kg, respectively. The relatively high contents of PET and DEHP were found near the Haihe River estuary, indicating the importance of riverine input. The PET and DEHP profiles in the cores dated by the 210Pb method showed increasing trends with time. The PET in Bohai Bay was low risk evaluated by the potential ecological risk assessment. Low ecological risks of DEHP to the benthic organisms were found in the sediments, using the environmental risk limits, risk quotient, threshold effect level and probable effect level methods. The pollution levels of PET and DEHP in Bohai Bay obtained in this study may provide important data for making pollution control strategies.

Riverine flux of dissolved phosphorus to the coastal sea may be overestimated, especially in estuaries of gated rivers: Implications of phosphorus adsorption/desorption on suspended sediments.

The flux of terrestrial dissolved inorganic phosphorous (DIP, i.e. PO43-) via rivers into coastal seas is usually calculated by simply multiplying its concentration with the corresponding water flow at the river mouth. Subsequent adsorption/desorption of DIP onto suspended sediment and the influence of salinity in the estuary are often overlooked. A series of DIP adsorption/desorption experiments under different salinities (0, 5, 15, 30) and suspended sediment concentrations (1-40 g L-1) were conducted in order to assess the potential influence of these factors on the overall DIP loading to the coastal zone. The effect of different sea-salt ions on DIP adsorption/desorption was also assessed by comparing different experimental solutions (NaCl solution, artificial seawater and real seawater). In estuaries, the adsorption of DIP to suspended sediments was greater than desorption, and the net adsorption increased with increasing concentration of suspended sediments and salinity. This enhanced DIP adsorption onto suspended sediment reduces the riverine discharge of DIP to coastal ecosystems. Disregarding this process, especially for the gated estuaries with high sediment resuspension, potentially leads to an overestimation of the terrestrial DIP input to the coastal region.

Human genetic variant E756del in the ion channel PIEZO1 not associated with protection from severe malaria in a large Ghanaian study.

Recently, a common genetic variant E756del in the human gene PIEZO1 was associated with protection from severe malaria. Here, we performed a genetic association study of this gain-of-function variant in a large case-control study including 4149 children from the Ashanti Region in Ghana, West Africa. The statistical analysis did not indicate an association with protection from severe malaria and, thus, providing evidence against a strong protective effect of the PIEZO1 E756del variant on severe malaria susceptibility.

The prevalence and clinical relevance of hyperhomocysteinemia suggesting vitamin B12 deficiency in presumed healthy infants.

BACKGROUND: Previous studies have demonstrated a high prevalence of biochemical vitamin B12 deficiency in infants in Norway. Increased total homocysteine (tHcy) is the most important marker of B12 deficiency in infants. There is a need to evaluate its clinical relevance. AIMS: To investigate the prevalence of hyperhomocysteinemia (S-tHcy > 8 µmol/L) suggestive of suboptimal B12 status and the prevalence of clinically relevant hyperhomocysteinemia in presumed healthy infants in Norway. Further, to evaluate risk factors, presence of symptoms and psychomotor development in these children. METHODS: In a prospective study we clinically examined 252 infants aged 3-7 months using standardized neurological and psychomotor tests prior to analyzing biochemical B12 deficiency markers in 250 infants. RESULTS: Twenty-five of 250 (10%) infants had hyperhomocysteinemia combined with clinically relevant symptoms suggestive of B12 deficiency. Hyperhomocysteinemia was associated with tremor, excessive sleep, and sub-normal scores in the fine motor section of the Ages and Stages Questionnaire. One-hundred and fourteen of 250 (46%) infants had hyperhomocysteinemia. Multiple regression analysis showed months of infant formula use as the strongest negative predictor for hyperhomocysteinemia. CONCLUSION: We have demonstrated associations between symptoms suggestive of infant B12 deficiency and increased levels of tHcy in presumed healthy infants The combination of hyperhomocysteinemia and associated relevant symptoms suggestive of B12 deficiency was a common finding, albeit most infants with hyperhomocysteinemia did not show symptoms.

Immune infiltrates in patients with localised high-risk soft tissue sarcoma treated with neoadjuvant chemotherapy without or with regional hyperthermia: A translational research program of the EORTC 62961-ESHO 95 randomised clinical trial.

BACKGROUND: The EORTC 62961-ESHO 95 randomised trial showed improved long-term survival of patients with high-risk soft-tissue sarcoma by adding regional hyperthermia to neoadjuvant chemotherapy. We hypothesised that immune infiltrate of patients treated with neoadjuvant therapy associate with clinical outcome. METHODS: Tumour infiltrating lymphocytes (TILs) and CD8, FOXP3, PD-1, and PD-L1 were evaluated in sequential biopsies of patients after four cycles of therapy. RESULTS: From a subgroup of 109 patients who had been randomised between July 1997 and November 2006 to neoadjuvant chemotherapy (53 patients) or neoadjuvant chemotherapy with regional hyperthermia (56 patients), 137 biopsies were obtained. TILs increased in paired second biopsies independent of treatment allocation (p < 0.001). FOXP3 regulatory T cells decreased (p = 0.002), and PD-L1 expression of tumours became undetectable. In the multivariate analysis, post-treatment high TILs correlated to LPFS (HR: 0.34; 95% CI 0.15-0.75; p = 0.008) and DFS (HR: 0.38; 95% CI 0.17-0.82; p = 0.015). In comparing post-treatment immune infiltrate between treatment arms, tumour response was associated with neoadjuvant chemotherapy with regional hyperthermia (p = 0.013) and high TILs (p = 0.064). High CD8 cell infiltration was associated with improved LPFS (HR: 0.27; 95% CI 0.09-0.79; Log-rank p = 0.011) and DFS (HR: 0.25; 95% CI 0.09-0.73; Log-rank p = 0.006). Improved survival at 10 years was associated with immune infiltrate after neoadjuvant chemotherapy with regional hyperthermia. CONCLUSION: Preoperative therapy re-programs a non-inflamed tumour at baseline into an inflamed tumour. The post-treatment immune infiltrate became predictive for clinical outcomes. The combination with regional hyperthermia primes the tumour microenvironment, enabling enhanced anti-tumour immune activity in high-risk soft tissue sarcomas. TRIAL REGISTRATION: ClinicalTrials.gov, NCT00003052.

Season of Data Collection of Child Dietary Diversity Indicators May Affect Conclusions About Longer-Term Trends in Peru, Senegal, and Nepal.

BACKGROUND: The WHO-UNICEF minimum dietary diversity (MDD) indicator for children aged 6-23 mo is a global monitoring indicator used to track multi-year population-level changes in dietary quality, but the influence of seasonality on MDD estimates remains unclear. OBJECTIVES: To examine how seasonality of data collection may influence population-level MDD estimates and inferences about MDD changes over multiple survey years. METHODS: We selected countries with 3 or more consecutive years of MDD data collection, including continuous national Demographic Health Surveys in Senegal (2012-2017; n = 12,183) and Peru (2005-2016; n = 35,272) and the Policy and Science for Health, Agriculture, and Nutrition sentinel site seasonal surveys (covering 3 seasons/y) in Nepal (2013-2016; n  = 1309). The MDD prevalence (≥5 of 8 food groups) and an 8-item continuous Food Group Score (FGS) and 95% CIs were estimated by month and compared for lean and non-lean seasons using ordinary least squares regression with dummy variables for year. RESULTS: The national prevalence of MDD was higher in Peru (75.4%) than in Nepal (39.1%) or in Senegal (15.7%). Children in Peru were 1.8% (coefficient, -0.0179; 95% CI, -0.033 to -0.002) less likely to achieve MDD during the lean season. Similar seasonal magnitudes were observed in Senegal (coefficient, -0.0347; 95% CI, -0.058 to -0.011) and Nepal (coefficient, -0.0133; 95% CI, -0.107 to 0.081). The FGS was about 0.1 item lower during the lean season in all 3 countries. In comparison, MDD increased by an average rate of only 4.2 and 4.4 percentage points per 5 y in Peru and Senegal, respectively. Intakes of specific food groups were stable across months in all countries, with the provitamin A-rich food group exhibiting the most seasonality. CONCLUSIONS: The magnitude of seasonal variation in MDD prevalence was smaller than expected but large relative to longer-term changes. If large-scale surveys are not conducted in the same season, biased conclusions about trends are possible.